Formulations of nebivolol

ABSTRACT

The present disclosure provides a formulation comprising: 0.05 to 10% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof; 0.4 to 10% (w/w) of a solubilizer; and 5 to 90% (w/w) of a sweetener, wherein the formulation has pH in the range of 3 to 7. The present disclosure provides a reconstituted formulation comprising the formulation with a liquid vehicle. The present disclosure also provides process of preparing the formulations and methods thereof.

FIELD OF INVENTION

The present disclosure relates to formulations of Nebivolol orpharmaceutically acceptable salts thereof. The present disclosure inparticular relates to oral formulations of Nebivolol or pharmaceuticallyacceptable salts thereof. The present disclosure further relates toprocess of preparing the formulations and implementations of theformulations thereof.

BACKGROUND OF THE INVENTION

Nebivolol is chemically known as(1RS,1′RS)-1,1′-[(2RS,2′SR)-bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)]-2,2′-iminodiethanolhydrochloride. Nebivolol is a racemate composed of d-Nebivolol and1-Nebivolol with the stereochemical designations of [SRRR]-nebivolol and[RSSS]-nebivolol, respectively. Nebivolol's molecular formula is(C₂₂H₂₅F₂NO₄·HCl) with the following structural formula.

Nebivolol is a highly selective beta-1 blocker and is mainly used forthe treatment and prevention of coronary vascular disorders. Nebivololis indicated for the treatment of hypertension, to lower blood pressureand may be used alone or in combination with other antihypertensiveagents. It is taken once or twice a day as per the requirement of thepatient.

In extensive metabolizers (most of the population) and at doses lessthan or equal to 10 mg, Nebivolol is preferentially β1 selective. Inpoor metabolizers and at higher doses, Nebivolol inhibits both β1- andβ2-adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic andmembrane stabilizing activity at therapeutically relevantconcentrations. At clinically relevant doses, Nebivolol does notdemonstrate al-adrenergic receptor blockade activity. Variousmetabolites, including glucuronides, contribute to β-blocking activity.

A major problem in the development of pharmaceutical compositionscomprising Nebivolol is its poor solubility and, concomitantly, the poorrelease and low bioavailability of the active ingredient. Pharmaceuticalcompositions containing Nebivolol are currently marketed in the US andvarious other countries under the brand name “Bystolic®” in the form oftablets.

It is generally known that certain segments of the population havedifficulty in ingesting and swallowing solid oral dosage forms such astablets and capsules. As many as a quarter of the total population hasthis difficulty. Further, solid dosage forms are not recommended forchildren or elderly due to increased risk in choking. Often, this leadsto non-compliance with the recommended medical therapy with the soliddosage forms, thereby resulting in rending the therapy ineffective.Further Nebivolol is bitter in taste. There has been a long-left needfor taste masked oral liquid formulation of Nebivolol for treatinghypertension. This approach leads to good results for geriatric patientswho cannot swallow tablets or capsules especially when they are certaindimensional limits.

Nebivolol and its tablet formulation is first disclosed in U.S. Pat. No.4,654,362A. U.S. Pat. No. 6,545,040 discloses method of lowering theblood pressure using Nebivolol.

U.S. Pat. No. 8,633,241B2 disclose solid oral dosage form of Nebivololhydrochloride without the use of wetting agent, and optionally usingbinder and/or disintegrant.

WO 2006/084684A1 disclose pharmaceutical compositions comprisingNebivolol and a hydrophilic polymer.

The oral liquid formulations are advantageous over conventional soliddosage administration of Nebivolol due to ease of administration, anincreased patient compliance to medication and accessibility toadditional patient populations such as to children and the elderly.

Hence there is a dire need in the state of art to provide stableNebivolol oral liquid formulations in the form of fully liquid as wellas powder formulations for reconstitution for oral liquidadministration.

SUMMARY OF THE INVENTION

In first aspect of the present disclosure, there is provided aformulation comprising: a) 0.05 to 10% (w/w) of Nebivolol or apharmaceutically acceptable salt thereof; b) 0.4 to 10% (w/w) of asolubilizer; and c) 5 to 90% (w/w) of a sweetener, wherein theformulation has pH in the range of 3 to 7.

In second aspect of the present disclosure, there is provided areconstituted formulation comprising the formulation comprising: a) 0.05to 10% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof;b) 0.4 to 10% (w/w) of a solubilizer; c) 5 to 90% (w/w) of a sweetener;d) 0.05 to 20% (w/w) of a flavouring agent; e) 0.05 to 20% (w/w) of apreservative; f) 0.5 to 20% (w/w) of a binder; g) 0.025 to 15% (w/w) ofa buffer; h) 0.1 to 3.0% (w/w) of a glidant; and i) 0.01 to 2% (w/w) ofa coloring agent, wherein the formulation has pH in the range of 3 to 7.

In third aspect of the present disclosure, there is provided areconstituted formulation comprising the formulation comprising: a) 0.05to 10% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof;b) 0.4 to 10% (w/w) of a solubilizer; c) 5 to 90% (w/w) of a sweetener;d) 0.05 to 20% (w/w) of a flavouring agent; e) 0.05 to 20% (w/w) of apreservative; f) 0.5 to 20% (w/w) of a binder; g) 0.025 to 15% (w/w) ofa buffer; h) 0.1 to 3.0% (w/w) of a glidant; i) 0.01 to 2% (w/w) of acoloring agent; and j) 65 to 95% (w/w) of a liquid vehicle, wherein theformulation has pH in the range of 3 to 7.

In fourth aspect of the present disclosure, there is provided aformulation comprising: a) 0.05 to 10% (w/w) of Nebivolol or apharmaceutically acceptable salt thereof; b) 0.4 to 10% (w/w) of asolubilizer; and c) 5 to 90% (w/w) of a sweetener, reconstituted with aliquid vehicle, wherein the reconstituted formulation is stable for atime period in the range of 30 days to one year; and the formulation haspH in the range of 3 to 7.

In fifth aspect of the present disclosure, there is provided a processof preparing the formulation comprising: a) 0.05 to 10% (w/w) ofNebivolol or a pharmaceutically acceptable salt thereof; b) 0.4 to 10%(w/w) of a solubilizer; and c) 5 to 90% (w/w) of a sweetener, whereinthe formulation has pH in the range of 3 to 7, the process comprising:i) adding nebivolol or a pharmaceutically acceptable salt thereof with asolubilizer to obtain a first mixture; and ii) blending the firstmixture with a sweetener to obtain the formulation.

In sixth aspect of the present disclosure, there is provided apharmaceutical composition comprising the formulation comprising: a)0.05 to 10% (w/w) of Nebivolol or a pharmaceutically acceptable saltthereof; b) 0.4 to 10% (w/w) of a solubilizer; and c) 5 to 90% (w/w) ofa sweetener, with other pharmaceutically active compound, wherein theformulation has pH in the range of 3 to 7.

In seventh aspect of the present disclosure, there is provided use ofthe formulation comprising: a) 0.05 to 10% (w/w) of Nebivolol or apharmaceutically acceptable salt thereof, b) 0.4 to 10% (w/w) of asolubilizer; and c) 5 to 90% (w/w) of a sweetener, wherein theformulation has pH in the range of 3 to 7, as a beta-blocker and/or forabnormal blood pressure.

In eighth aspect of the present disclosure, there is provided a kitcomprising: a) the formulation comprising: i) 0.05 to 10% (w/w) ofNebivolol or a pharmaceutically acceptable salt thereof; ii) 0.4 to 10%(w/w) of a solubilizer; and iii) 5 to 90% (w/w) of a sweetener; and b) aliquid vehicle, wherein the formulation has pH in the range of 3 to 7.

In ninth aspect of the present disclosure, there is provided an oralpharmaceutical dosage form comprising a dosing unit comprising theformulation comprising: a) 0.05 to 10% (w/w) of Nebivolol or apharmaceutically acceptable salt thereof; b) 0.4 to 10% (w/w) of asolubilizer; and c) 5 to 90% (w/w) of a sweetener, wherein theformulation has pH in the range of 3 to 7; and Nebivolol or apharmaceutically acceptable salt thereof is in a final concentrationequivalent to between 0.1 mg nebivolol HCl per ml liquid vehicle and 50mg nebivolol HCl per ml liquid vehicle.

In tenth aspect of the present disclosure, there is provided a method ofadministration in an individual in need thereof, the method comprising:administering a first amount of the formulation comprising: a) 0.05 to10% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof; b)0.4 to 10% (w/w) of a solubilizer; and c) 5 to 90% (w/w) of a sweetener,wherein the first amount of the formulation comprises Nebivolol or apharmaceutically acceptable salt thereof in a final concentrationequivalent to between 0.1 mg nebivolol HCl per ml liquid vehicle and 50mg nebivolol HCl per ml liquid vehicle.

In eleventh aspect of the present disclosure, there is provided a methodof treating or preventing a condition, disorder, or disease mediated bybeta-blocking, the method comprising: administering an effective amountof the formulation comprising: a) 0.05 to 10% (w/w) of Nebivolol or apharmaceutically acceptable salt thereof; b) 0.4 to 10% (w/w) of asolubilizer; and c) 5 to 90% (w/w) of a sweetener, wherein theformulation has pH in the range of 3 to 7 or the pharmaceuticalcomposition, to a subject in need thereof.

These and other features, aspects, and advantages of the present subjectmatter will be better understood with reference to the followingdescription and appended claims. This summary is provided to introduce aselection of concepts in a simplified form. This summary is not intendedto identify key features or essential features of the claimed subjectmatter, nor is it intended to be used to limit the scope of the claimedsubject matter.

DETAILED DESCRIPTION OF THE INVENTION

Those skilled in the art will be aware that the present disclosure issubject to variations and modifications other than those specificallydescribed. It is to be understood that the present disclosure includesall such variations and modifications. The disclosure also includes allsuch steps, features, compositions, and compounds referred to orindicated in this specification, individually or collectively, and anyand all combinations of any or more of such steps or features.

Definitions

For convenience, before further description of the present disclosure,certain terms employed in the specification, and examples are delineatedhere. These definitions should be read in the light of the remainder ofthe disclosure and understood as by a person of skill in the art. Theterms used herein have the meanings recognized and known to those ofskill in the art, however, for convenience and completeness, particularterms and their meanings are set forth below.

The articles “a”, “an” and “the” are used to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle.

The terms “comprise” and “comprising” are used in the inclusive, opensense, meaning that additional elements may be included. It is notintended to be construed as “consists of only”.

Throughout this specification, unless the context requires otherwise theword “comprise”, and variations such as “comprises” and “comprising”,will be understood to imply the inclusion of a stated element or step orgroup of element or steps but not the exclusion of any other element orstep or group of element or steps.

The term “including” is used to mean “including but not limited to”.“Including” and “including but not limited to” are used interchangeably.

The term “at least one” is used to mean one or more and thus includesindividual components as well as mixtures/combinations.

Nebivolol as used herein may be present in crystallize or amorphousform. The particle size of Nebivolol used as per the invention may rangefrom 1 to 100 microns, preferably, d90 less than 20 microns. The majorimpurities of Nebivolol are Desfluoro Nebivolol and 4-BenzylatedNebivolol. The oral liquid formulations of the present invention arestable and the presence these impurities are less than 1%.

The term “pharmaceutically acceptable salts thereof” as used hereinrefers to compounds or compositions that are physiologically tolerableand do not typically produce allergic or similar untoward reaction,including but not limited to gastric upset or dizziness whenadministered to subjects. Pharmaceutically acceptable salts forming partof this invention include addition salts derived from acids, forexample, inorganic acids, such as hydrohalic acid, e.g. hydrochloric,hydrobromic and the like, and sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propane-tricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. In thepresent disclosure, pharmaceutically acceptable salts thereof includesbut not limited to salts of Nebivolol selected from hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, aceticacid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid,2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioicacid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,4-methylbenzenesulfonic acid, 2-hydroxybenzoic acid, or4-amino-2-hydroxybenzoic acid. In the present disclosure, the amount ofNebivolol included in the formulation, as calculated on the basis of theHCl salt, is from about 0.1 mg/mL to 50 mg/mL, may be 1 mg/ml, 0.8mg/ml, 40 mg/ml, 30 mg/ml, 20 mg/ml, 10 mg/ml, and the like.

The term “solubilizer” as used herein refers to solubility enhancerSolubilizer or solubility enhancer and may be used interchangeably.Suitable solubilizer or solubility enhancers include water-solubleorganic solvents such as polyethylene glycol 300, polyethylene glycol400, ethanol, propylene glycol, glycerin; anionic surfactant such assodium lauryl sulfate, docusate sodium and the like; non-ionicsurfactants such as Cremophor EL, Cremophor RH 40, Cremophor RH 60,d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20,polysorbate 80, sorbitan monooleate, poloxamer, poloxamer 188, poloxamer407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14,Softigen 767, and mono- and di-fatty acid esters such as polyethyleneglycol PEG 300, PEG 400, PEG 1750, or PEG 4000, cyclodextrin, Captisoland the like.

The term “sweetener” as used herein refers to a substance providingsweet taste and has taste similar to a sugar to make the product morepalatable. This includes natural and synthetic sugars, natural andartificial sweeteners, natural extracts, and any material that initiatesa sweet sensation in a subject. In some implementation, a solid/powdersweetener is used in the oral liquid formulation and a liquid sweeteneris used in the oral liquid formulation described herein. The amount ofsweetener may vary depending on the sweetener used and may range from 1mg to 500 mg/ml, 1 mg to 400 mg/ml, or 10 mg to 350 mg/ml.

Sweeteners or sugars illustratively include glucose, fructose, sucrose,xylitol, tagatose, sucralose, maltitol, isomaltulose, isomaltulose,lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose,and the like. Other sweeteners illustratively include glycerin, inulin,erythritol, acesulfame, and salts thereof, e.g., acesulfame potassium,alitame, aspartame, neotame, sodium cyclamate, saccharin and saltsthereof, e.g., saccharin sodium or saccharin calcium, neohesperidindihydrochalcone, stevioside, thaumatin, and the like. Sweeteners can beused in the form of crude or refined products such as hydrogenatedstarch hydrosylates, maltitol syrup, high fructose corn syrup, and asbranded proprietary blend products. Sweeteners can be used singly orcombinations of two or more. Suitable concentrations of differentsweeteners can be selected based on published information,manufacturers' data sheets, and by routine testing.

The term “flavouring agent” as used herein refers to a substance thatprovides enhanced the taste or aroma to the formulation. Non-limitingexamples of suitable natural flavors, some of which can be readilysimulated with synthetic agents or combinations thereof, include almond,anise, apple, apricot, banana, blackberry, blackcurrant, blueberry,caramel, cherry, chocolate, cinnamon, cranberry, grape, lemon, lime,orange, peppermint, pineapple, raspberry, spearmint, strawberry,vanilla, etc. Also useful, particularly where the composition isintended primarily for pediatric use is tutti-frutti or bubble gumflavor, a compounded flavoring agent based on fruit flavors. Presently,preferred flavoring agents include bubble gum, strawberry, cherry,grape, orange, peppermint, and vanilla. In some implementation, theresultant liquid form from the Nebivolol hydrochloride powder orgranules described herein comprises a grape (specifically, white grape)flavoring agent. Flavoring agents may be used singly or in combinationsof two or more.

The term “preservative” as used herein refers to a compound thatprovides anti-microbial effect to the formulation. preservative is usedin an amount sufficient to provide antimicrobial effectiveness to theNebivolol oral liquid formulation described herein. Preservativesinclude anti-microbials, anti-oxidants, and agents that enhancesterility. Suitable preservatives include ascorbic acid, ascorbylpalmitate, benzyl alcohol butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), erythorbic acid, fumaric acid, malic acid, propylgallate, sodium ascorbate, sodium benzoate, sodium bisulfate, sodiummetabisulfite, sodium sulfite, methyl paraben, propylparaben, benzoicacid, potassium sorbate, and vanillin. In some implementation, theNebivolol hydrochloride powder described herein, when compounded into aliquid form, or in multiple dosage form comprises a preservative. Theamount of preservative used may range from about 0.5 to 20 mg/ml.

The term “binder” or “thickener” as used herein refers to substance thatimpart viscosity or weight to the formulation. Exemplarybinders/thickeners include dextrin, cellulose derivatives (hydroxypropylcellulose, ethylcellulose, hydroxyethyl cellulose, methylcellulose,polyvinylpyrrolidone (povidone or PVP K-90), hypromellose, and the like)starches, gelatin, pectin, polyethylene oxide, and certain gums (xanthangum, locust bean gum, etc).

The term “buffer” or “buffering agent” as used herein refers to asubstance or compound used to maintain the pH of the formulation.Buffering agents maintain the pH when Nebivolol hydrochloride powder iscompounded into a liquid form or the liquid solution or suspension.Examples of suitable buffering agents include, but are not limited to,sodium bicarbonate, potassium bicarbonate, magnesium hydroxide,magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminumhydroxide/sodium bicarbonate precipitate, a mixture of an amino acid anda buffer, a mixture of aluminum glycinate and a buffer, a mixture ofacid salt and an amino acid and a buffer, and a mixture of an alkalisalt of an amino acid and a buffer. Additional buffering agents includecitric acid, sodium citrate, sodium tartrate, sodium acetate, sodiumcarbonate, sodium polyphosphate, potassium polyphosphate, sodiumpyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate,trisodium phosphate or sodium phosphate, tripotassium phosphate, sodiumacetate, potassium metaphosphate, magnesium oxide, magnesium carbonate,magnesium silicate, calcium acetate, calcium glycerophosphate, calciumchloride, calcium hydroxide, calcium lactate, calcium carbonate, calciumbicarbonate, and other calcium salts. Some buffering agents also imparteffervescent qualities when Nebivolol hydrochloride powder is compoundedinto a liquid. In some implementation, the Nebivolol hydrochloridepowder described herein, when compounded into a liquid form, comprises abuffering agent. The amount of buffer used may range from 0.1 mg to 100mg/ml, preferably 1 mg to 50 mg, 2 mg to 50 mg/ml.

The term “coloring agent” as used herein refers to a substance added toidentity and/or for aesthetic purposes. Suitable coloring agentsapproved by the U.S. Food and Drug Administration (FDA) include FD&C RedNo. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C BlueNo. 2, D&C Green No. 5, D&C Orange No. 5, D&C Yellow No. 10, caramel,ferric oxide and mixtures thereof. The resultant liquid form from theNebivolol hydrochloride powder/granules described herein displays anamber-colored appearance for identity and aesthetic purposes associatedwith a white grape flavor.

The term “glidant” as used herein refers to substances that improveflowability of a powder. Suitable glidants include, but are not limitedto, calcium phosphate tribasic, calcium silicate, cellulose (powdered),colloidal silicon dioxide, magnesium silicate, magnesium trisilicate,silicon dioxide, starch, talc, and the like.

The term “liquid vehicle” or “diluent” as used herein refers to asolvent or liquid present in the formulation, and the formulation is inliquid form. Liquid vehicles/diluent for compounding the Nebivololpowder formulations into an oral solution are also described herein.Exemplary liquid vehicles include water, ethyl alcohol, glycerin, syrup(sugar or other sweetener based, e.g., Ora-Sweet® SF sugar-free flavoredsyrup), juices (apple, grape, orange, cranberry, cherry, tomato and thelike), other beverages (tea, coffee, soft drinks, milk and the like),oils (olive, soybean, corn, mineral, castor and the like), andcombinations or mixtures thereof.

Certain liquid vehicles, e.g., oil and water, can be combined togetherto form emulsions. In some implementation, water is used for as avehicle for a Nebivolol oral liquid formulation. In otherimplementation, a syrup is used for as a vehicle for a Nebivolol oralliquid formulation. In yet other implementation, a juice is used for asa vehicle for a Nebivolol oral liquid formulation. The liquid isselected for a particular oral liquid formulation (solution, suspension,etc.) as well as other qualities such as clarity, toxicity, viscosity,compatibility with excipients, chemical inertness, palatability, odor,color and economy. The liquid vehicle optionally comprising one or moreexcipients selected from flavouring agent, preservative, binder, buffer,coloring agent, glidant, or combination thereof.

The term “pharmaceutically active compound” used herein refers to othercompounds that are pharmaceutically active and that can be used incombination with the formulation of the present disclosure. The otherpharmaceutically active compounds include but not limited to diureticssuch as loop, thiazide, potassium-sparing, and the like, beta blockerssuch as metoprolol, propanolol, pronethalol, and the like, alphablockers such as phentolamine, phenoxybenzamine, tamsulosin, prazosin,and the like, mixed alpha and beta blockers such as bucindolol,carvedilol, labetalol, calcium channel blockers such as dihydropyridinessuch as nifedipine, amlodipine, etc., dilitazem, verapamil and the like,angiotensin II receptor antagonists such as saralasin, losartan,eprosartin, irbesartan, valsartan, and the like), other ACE inhibitorssuch as captopril, lisinopril, quinapril, ramipril, enalapril,zofenopril, and the like), aldosterone antagonists such as eplerenone,spironolactone and the like, vasodilators such as hydralazine and thelike, or alpha-2 agonists such as clonidine, moxonidine, guanabenz andthe like

The compounded solution of the invention is prepared by mixing a powderform of Nebivolol hydrochloride with a liquid solution, also referred toas a diluent. The liquid solution or diluent of the invention impartsimproved properties on the compounded solution. An optimal liquidsolution can impart on the compounded solution enhanced stability atroom temperature without interfering with the activity of the Nebivololhydrochloride.

Ratios, concentrations, amounts, and other numerical data may bepresented herein in a range format. It is to be understood that suchrange format is used merely for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limits of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that rangeas if each numerical value and sub-range is explicitly recited. Forexample, a weight percentage range of 0.05 to 10% (w/w) should beinterpreted to include not only the explicitly recited limits of 0.05%(w/w) to 10% (w/w) but also to include sub-ranges, such as 0.06% to 9%(w/w), 0.1% to 7% (w/w) and so forth, as well as individual amounts,including fractional amounts, within the specified ranges, such as0.062%, 0.09%, 0.88%, 0.9%, and 1.39% for example.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the disclosure, the preferred methods, andmaterials are now described. All publications mentioned herein areincorporated herein by reference.

The present disclosure is not to be limited in scope by the specificimplementation described herein, which are intended for the purposes ofexemplification only. Functionally-equivalent products, compositions,and methods are clearly within the scope of the disclosure, as describedherein.

As discussed in the background, pediatric and geriatric populationsencounter difficulty being administered solid oral dosage forms such ascapsules. And also the solid dosage forms are not recommended forchildren or elderly due to increased risk of choking. This may lead tonon-compliance with the recommended pharmacotherapy with the solid oraldosage forms and likely results in rendering the therapy ineffective.Additionally, certain solid oral dosage forms of medications cannot beadministered simply by crushing (for example patients requiring varioustypes of feeding tubes), because of the coating or drug deliverymechanism by which the drug is released. To overcome disadvantagesassociated with the use of the tablet form, compounding pharmacistpulverizes and crush the tablet(s) into a powder via mortar and pestleand reconstitute the powder in some liquid form. However, forming anoral liquid in this fashion has significant drawbacks including largevariability in the actual dosage, incomplete solubilizing of the tabletin the liquid, rapid instability, inconsistent formulation methods percompounding pharmacy, and a number of other potential issues. Thecrushed tablet liquid formulation may also be potentially unsafe due tocontamination with residual drugs and other substances from the mortarand pestle or another crushing agent. Thus, the present inventionovercomes aforementioned drawbacks of the solid oral dosage form ofNebivolol hydrochloride by providing a formulation comprising Nebivololwith a solubilizer and a sweetener. The present invention also providesa formulation with a liquid vehicle.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.05 to 10% (w/w) of Nebivolol ora pharmaceutically acceptable salt thereof; b) 0.4 to 10% (w/w) of asolubilizer; and c) 5 to 90% (w/w) of a sweetener, wherein theformulation has pH in the range of 3 to 7. In an alternateimplementation, there is provided a formulation comprising: a) 0.05 to5% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof; b)0.4 to 9% (w/w) of a solubilizer; and c) 5 to 89% (w/w) of a sweetener.In other implementation, there is provided a formulation comprising: a)0.05 to 4% (w/w) of Nebivolol or a pharmaceutically acceptable saltthereof; b) 0.5 to 9% (w/w) of a solubilizer; and c) 6 to 89% (w/w) of asweetener.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein Nebivolol or apharmaceutically acceptable salt thereof is Nebivolol hydrochloride.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.05 to 10% (w/w) of Nebivolol ora pharmaceutically acceptable salt thereof; b) 0.4 to 10% (w/w) of asolubilizer; c) 5 to 90% (w/w) of a sweetener; d) 0.05 to 20% (w/w) of aflavouring agent; e) 0.05 to 20% (w/w) of a preservative; f) 0.5 to 20%(w/w) of a binder; g) 0.025 to 15% (w/w) of a buffer; h) 0.1 to 3.0%(w/w) of a glidant; and i) 0.01 to 2% (w/w) of a coloring agent, whereinthe formulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.05 to 10% (w/w) of Nebivolol ora pharmaceutically acceptable salt thereof; b) 0.4 to 10% (w/w) of asolubilizer; c) 5 to 90% (w/w) of a sweetener; d) 0.05 to 20% (w/w) of aflavouring agent; e) 0.05 to 20% (w/w) of a preservative; f) 0.5 to 20%(w/w) of a binder; g) 0.025 to 15% (w/w) of a buffer; h) 0.1 to 3.0%(w/w) of a glidant; i) 0.01 to 2% (w/w) of a coloring agent; and j) 65to 95% (w/w) of a liquid vehicle, wherein the formulation has pH in therange of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the solubilizer isselected from cyclodextrin, propylene glycol, polyethylene glycol,polysorbate 20, polysorbate 80, sorbitan monooleate, poloxamer, sodiumlauryl sulfate, captisol, labrasol, or combinations thereof, and thesweetener is selected from natural and synthetic sugars, natural andartificial sweeteners, natural extracts. In another implementation ofthe present disclosure, there is provided a formulation as disclosedherein, wherein the solubilizer is selected from sodium lauryl sulfate,propylene glycol, polyethylene glycol, poloxamer, or combinationsthereof.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the sweetener isselected from glucose, fructose, sucrose, xylitol, tagatose, sucralose,maltitol, isomaltulose, isomaltulose, lactitol, sorbitol, eiythritol,trehalose, maltodextrin, polydextrose, glycerin, inulin, erythritol,acesulfame, saccharin sodium, saccharin calcium, neohesperidindihydrochalcone, stevioside, thaumatin, or combinations thereof. Inanother implementation of the present disclosure, there is provided aformulation as disclosed herein, wherein the sweetener is selected fromsorbitol, xylitol, sucralose, maltitol, saccharin sodium, orcombinations thereof.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulationcomprises one or more liquid vehicle.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulationcomprises one or more liquid vehicle selected from water, ethyl alcohol,glycerin, syrup, beverage, juices, or combinations thereof in the weightrange of 65 to 95% (w/w) of the formulation. In an alternateimplementation, the formulation comprises a liquid vehicle in the weightrange of 65 to 94% (w/w) of the formulation. In another alternateimplementation, the formulation comprises a liquid vehicle in the weightrange of 65 to 93% (w/w) of the formulation. In one another alternateimplementation, the formulation comprises a liquid vehicle in the weightrange of 67 to 90% (w/w) of the formulation.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulationcomprises water or juice as liquid vehicle. In an alternateimplementation, there is provided a formulation as disclosed herein,wherein the formulation comprises water as liquid vehicle.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulationcomprises an excipient selected from a flavouring agent, a preservative,a binder, a buffer, a glidant, a coloring agent, or combinationsthereof.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the flavouring agentis in the weight range of 0.05 to 20% (w/w) of the formulation; thepreservative is in the weight range of 0.05 to 20% (w/w) of theformulation; the binder is in the weight range of 0.5 to 20% (w/w) ofthe formulation; the buffer is in the weight range of 0.025 to 15% (w/w)of the formulation; the glidant is in the weight range of 0.1 to 3.0%(w/w) of the formulation; and the coloring agent is in the weight rangeof 0.01 to 2% (w/w) of the formulation. In an alternate implementation,there is provided a formulation as disclosed herein, wherein theflavouring agent is in the weight range of 0.05 to 15% (w/w) of theformulation; the preservative is in the weight range of 0.05 to 15%(w/w) of the formulation; the binder is in the weight range of 0.5 to15% (w/w) of the formulation; the buffer is in the weight range of 0.025to 10% (w/w) of the formulation; the glidant is in the weight range of0.1 to 2.0% (w/w) of the formulation; and the coloring agent is in theweight range of 0.01 to 1% (w/w) of the formulation.

In an alternate implementation, there is provided a formulation asdisclosed herein, wherein the flavouring agent is in the weight range of0.05 to 10% (w/w) of the formulation; the preservative is in the weightrange of 0.05 to 10% (w/w) of the formulation; the binder is in theweight range of 0.5 to 10% (w/w) of the formulation; the buffer is inthe weight range of 0.025 to 5% (w/w) of the formulation; the glidant isin the weight range of 0.1 to 1.0% (w/w) of the formulation; and thecoloring agent is in the weight range of 0.01 to 0.5% (w/w) of theformulation.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the flavouring agentis selected from strawberry, cherry, grape, orange, peppermint, vanilla,bubble gum, or combinations thereof. In an alternate implementation,there is provided a formulation as disclosed herein, wherein theflavouring agent is selected from strawberry, grape, orange, orcombinations thereof

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the preservative isselected from ascorbic acid, benzyl alcohol butylated hydroxyanisole(BHA), butylated hydroxytoluene (BUT), sodium benzoate, sodiumbisulfate, sodium metabisulfite, sodium sulfite, methyl paraben,propylparaben, benzoic acid, potassium sorbate, or combinations thereof.In an alternate implementation, there is provided a formulation asdisclosed herein, wherein the preservative is selected from sodiumbenzoate, methyl paraben, propylparaben, or combinations thereof.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the binder isselected from polyvinylpyrrolidone, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, methylcellulose, hypromellose,gelatine, starch, trehalose, gums, or combinations thereof. In analternate implementation, there is provided a formulation as disclosedherein, wherein the binder is polyvinylpyrrolidone.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the buffer isselected from citric acid, sodium bicarbonate, potassium bicarbonate,magnesium hydroxide, magnes citric acid, sodium citrate, sodiumtartrate, sodium acetate, sodium carbonate, sodium polyphosphate,potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate,disodium hydrogenphosphate, trisodium phosphate, tripotassium phosphate,sodium acetate, or combinations thereof. In an alternate implementation,there is provided a formulation as disclosed herein, wherein the bufferis selected from citric acid, sodium polyphosphate, sodiumpyrophosphate, trisodium phosphate, or combinations thereof.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the glidant isselected from calcium phosphate tribasic, calcium silicate, cellulose,colloidal silicon dioxide, magnesium silicate, magnesium trisilicate,silicon dioxide, starch, talc, or combinations thereof; and the coloringagent is selected from FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40,FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5,D&C Yellow No. 10, caramel, ferric oxide, or combinations thereof. In analternate implementation, there is provided a formulation as disclosedherein, wherein the glidant is silicon dioxide.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulationcomprises 0.1 to 50 mg/ml of Nebivolol or a pharmaceutically acceptablesalt thereof; 0.1 to 300 mg/ml of a solubilizer; and 5 to 400 mg/ml of asweetener.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulationcomprises 0.1 to 50 ml of the liquid vehicle. In an alternateimplementation, there is provided a formulation as disclosed herein,wherein the formulation comprises 0.1 to 45 ml of the liquid vehicle. Inanother implementation, there is provided a formulation as disclosedherein, wherein the formulation comprises 0.1 to 40 ml of the liquidvehicle.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulationcomprises 0.5 to 100 mg/ml of a flavouring agent; 0.5 to 50 mg/ml of apreservative; 0.5 to 20 mg/ml of a binder, 0.1 to 100 mg/ml of a buffer;0.025 to 10 mg/ml of a glidant; and 0.01 to 20 mg/ml of a coloringagent.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulation is astable oral formulation for administration as a liquid.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.1 to 50 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 0.1 to 300 mg/ml of asolubilizer; c) 0.5 to 400 mg/ml sweetener; d) 0.5 to 100 mg/ml of aflavouring agent; e) 0.5 to 50 mg/ml of a preservative; f) 0.5 to 20mg/ml of a binder, g) 0.1 to 100 mg/ml of a buffer; h) 0.025 to 10 mg/mlof a glidant; and i) 0.01 to 20 mg/ml of a coloring agent, wherein theformulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.1 to 50 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 0.1 to 300 mg/ml of asolubilizer; c) 0.5 to 400 mg/ml sweetener; d) 0.5 to 100 mg/ml of aflavouring agent; e) 0.5 to 50 mg/ml of a preservative; f) 0.5 to 20mg/ml of a binder, g) 0.1 to 100 mg/ml of a buffer; h) 0.025 to 10 mg/mlof a glidant; i) 0.01 to 20 mg/ml of a coloring agent; and j) 0.1 to 50ml of the liquid vehicle, wherein the formulation has pH in the range of3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.1 to 50 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 0.1 to 300 mg/ml of asolubilizer; c) 0.5 to 400 mg/ml sweetener; and d) 0.5 to 20 mg/ml of aflavouring agent, wherein the formulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.5 to 10 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 1 to 20 mg/ml of asolubilizer; c) 70 to 200 mg/ml sweetener; d) 1 to 5 mg/ml of aflavouring agent, and e) 7 to 12 mg/ml of a binder wherein theformulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.5 to 10 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 1 to 20 mg/ml of asolubilizer; c) 70 to 200 mg/ml sweetener; d) 1 to 5 mg/ml of aflavouring agent, and e) 7 to 12 mg/ml of a binder with the liquidvehicle in an amount ranging from Qs (quantity sufficient) to 1 ml,wherein the formulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.5 to 10 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 1 to 20 mg/ml of asolubilizer; c) 70 to 200 mg/ml sweetener; d) 0.5 to 1 mg/ml of aflavouring agent, and e) 0.5 to 1 mg/ml of a preservative, with theliquid vehicle in an amount ranging from Qs to 1 ml, wherein theformulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.5 to 10 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 5 to 20 mg/ml of asolubilizer; c) 70 to 200 mg/ml sweetener; d) 1 to 3 mg/ml of aflavouring agent; e) 0.5 to 2 mg/ml of a preservative; f) 0.1 to 1 mg/mlof a buffer; and j) Qs to 1 ml of the liquid vehicle, wherein theformulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.1 to 50 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 0.1 to 300 mg/ml of asolubilizer; c) 0.5 to 400 mg/ml sweetener; d) 0.5 to 100 mg/ml of aflavouring agent, e) 0.5 to 20 mg/ml of a binder; and the liquidvehicle, wherein the formulation has pH in the range of 3 to 7, and theformulation is homogenous and stable for at least 30 days at ambient andrefrigerated temperature and has 95% w/w or greater of the initialNebivolol amount and 5% w/w or less total impurities or relatedsubstances at the end of the given storage period.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.1 to 50 mg/ml Nebivolol or apharmaceutically acceptable salt thereof; b) 0.1 to 300 mg/ml of asolubilizer; c) 0.5 to 400 mg/ml sweetener; d) 0.5 to 100 mg/ml of aflavouring agent, e) 0.5 to 20 mg/ml of a binder; and the liquidvehicle, wherein the formulation has pH in the range of 3 to 7 and isstable at about 25±5° C. for a time period of one month to 12 months.

According to an implementation of the present disclosure, there isprovided a stable water soluble granule formulation comprising: a) 0.1to 50 mg/ml Nebivolol or a pharmaceutically acceptable salt thereof; b)0.1 to 300 mg/ml of a solubilizer; c) 0.5 to 400 mg/md sweetener; d) 0.5to 100 mg/ml of a flavouring agent, and e) 0.5 to 20 mg/ml of a binder,wherein the formulation has pH in the range of 3 to 7; and said granulesare administered as oral liquid by dissolving in the liquid vehicle.

According to an implementation of the present disclosure, there isprovided a reconstituted formulation comprising the formulationcomprising a) 0.05 to 10% (w/w) of Nebivolol or a pharmaceuticallyacceptable salt thereof; b) 0.4 to 10% (w/w) of a solubilizer; and c) 5to 90% (w/w) of a sweetener with a liquid vehicle, wherein thereconstituted formulation is stable for a time period in the range of 30days to one year, and the formulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation comprising: a) 0.1 to 2% (w/w) of Nebivolol or apharmaceutically acceptable salt thereof; b) 5 to 10% (w/w) of asolubilizer; c) 70 to 90% (w/w) of a sweetener; d) 0.1 to 1% (w/w) of aflavouring agent; and e) 0.5 to 1% (w/w) of a preservative, wherein theformulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a reconstituted formulation comprising (i) 5 to 35% (w/w) ofthe formulation comprising a) 0.05 to 10% (w/w) of Nebivolol or apharmaceutically acceptable salt thereof, b) 0.4 to 10% (w/w) of asolubilizer; and c) 5 to 90% (w/w) of a sweetener; and (ii) 65 to 95%(w/w) of the liquid vehicle, wherein the reconstituted formulation isstable for a time period in the range of 30 days to one year.

According to an implementation of the present disclosure, there isprovided a reconstituted formulation comprising the formulation a) 0.05to 10% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof;b) 0.4 to 10% (w/w) of a solubilizer; c) 5 to 90% (w/w) of a sweetener;d) 0.05 to 20% (w/w) of a flavouring agent; e) 0.05 to 20% (w/w) of apreservative; f) 0.5 to 20% (w/w) of a binder; g) 0.025 to 15% (w/w) ofa buffer; h) 0.1 to 3.0% (w/w) of a glidant; and i) 0.01 to 2% (w/w) ofa coloring agent, with a liquid vehicle, wherein the reconstitutedformulation is stable for a time period in the range of 30 days to oneyear, and the formulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a process of preparing the formulation comprising: a) 0.05 to10% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof; b)0.4 to 10% (w/w) of a solubilizer; and c) 5 to 90% (w/w) of a sweetener,wherein the formulation has pH in the range of 3 to 7, the processcomprising: i) adding nebivolol or a pharmaceutically acceptable saltthereof with a solubilizer to obtain a first mixture; and ii) blendingthe first mixture with a sweetener to obtain the formulation.

According to an implementation of the present disclosure, there isprovided a process of preparing the formulation comprising: a) 0.05 to10% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof; b)0.4 to 10% (w/w) of a solubilizer; and c) 5 to 90% (w/w) of a sweetener,wherein the formulation has pH in the range of 3 to 7, the processcomprising: i) adding nebivolol or a pharmaceutically acceptable saltthereof with a solubilizer to obtain a first mixture; and ii) blendingthe first mixture with a sweetener to obtain the formulation, whereinthe formulation is blended with an excipient selected from a flavoringagent, a preservative, a binder, a buffer, a glidant, a coloring agent,or combinations thereof.

According to an implementation of the present disclosure, there isprovided a process of preparing the formulation comprising: a) 0.05 to10% (w/w) of Nebivolol or a pharmaceutically acceptable salt thereof; b)0.4 to 10% (w/w) of a solubilizer; and c) 5 to 90% (w/w) of a sweetener,wherein the formulation has pH in the range of 3 to 7, the processcomprising: i) adding nebivolol or a pharmaceutically acceptable saltthereof with a solubilizer to obtain a first mixture; and ii) blendingthe first mixture with a sweetener to obtain the formulation, whereinthe formulation is diluted with a liquid vehicle.

According to an implementation of the present disclosure, there isprovided a process of preparing the formulation as disclosed herein, theprocess comprising: i) adding nebivolol or a pharmaceutically acceptablesalt thereof with a solubilizer to obtain a first mixture; and ii)blending the first mixture with a sweetener and diluted with a liquidvehicle to obtain the formulation, followed by addition of an excipientselected from a flavoring agent, a preservative, a binder, a buffer, aglidant, a coloring agent, or combinations thereof; and wherein theformulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a process of preparing the formulation as disclosed herein, theprocess comprising: i) adding nebivolol or a pharmaceutically acceptablesalt thereof with a solubilizer to obtain a first mixture; and ii) thefirst mixture is diluted with a liquid vehicle comprising the sweetenerto obtain the formulation; and wherein the formulation has pH in therange of 3 to 7.

According to an implementation of the present disclosure, there isprovided a process of preparing the formulation as disclosed herein, theprocess comprising: i) adding nebivolol or a pharmaceutically acceptablesalt thereof with a solubilizer to obtain a first mixture; and ii) thefirst mixture is diluted with the liquid vehicle comprising thesweetener, the flavoring agent, the preservative, the buffer, thecoloring agent, or combinations thereof; and wherein the formulation haspH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a process of preparing the formulation as disclosed herein, theprocess comprising: i) adding nebivolol or a pharmaceutically acceptablesalt thereof with a solubilizer to obtain a first mixture; and ii) thefirst mixture is diluted with the liquid vehicle comprising thesweetener, the flavoring agent, the preservative, the buffer, thebinder, the coloring agent, or combinations thereof, wherein theformulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a process of preparing the formulation as disclosed herein, theprocess comprising: i) adding nebivolol or a pharmaceutically acceptablesalt thereof with a solubilizer to obtain a first mixture; and ii)blending the first mixture with the sweetener, the flavoring agent, thepreservative, the buffer, the binder, the coloring agent, orcombinations thereof, wherein nebivolol or a pharmaceutically acceptablesalt thereof is mixed with a liquid vehicle prior to adding with thesolubilizer; and the formulation has pH in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulation isadministered orally.

According to an implementation of the present disclosure, there isprovided a formulation as disclosed herein, wherein the formulation is abeta-blocker with β-adrenergic blocking ability.

According to an implementation of the present disclosure, there isprovided a pharmaceutical composition comprising the formulation asdisclosed herein with other pharmaceutically active compound.

According to an implementation of the present disclosure, there isprovided use of the formulation as disclosed herein, as a beta-blockerand/or for abnormal blood pressures.

According to an implementation of the present disclosure, there isprovided a kit comprising: i) the formulation comprising a) 0.05 to 10%(w/w) of Nebivolol or a pharmaceutically acceptable salt thereof; b) 0.4to 10% (w/w) of a solubilizer; and c) 5 to 90% (w/w) of a sweetener,wherein the formulation has pH in the range of 3 to 7; and ii) a liquidvehicle.

According to an implementation of the present disclosure, there isprovided a kit comprising: i) the formulation comprising a) 0.05 to 10%(w/w) of Nebivolol or a pharmaceutically acceptable salt thereof; b) 0.4to 10% (w/w) of a solubilizer; c) 5 to 90% (w/w) of a sweetener; d) 0.05to 20% (w/w) of a flavouring agent; e) 0.05 to 20% (w/w) of apreservative; f) 0.5 to 20% (w/w) of a binder; g) 0.025 to 15% (w/w) ofa buffer; h) 0.1 to 3.0% (w/w) of a glidant; and i) 0.01 to 2% (w/w) ofa coloring agent, wherein the formulation has pH in the range of 3 to 7;and ii) a liquid vehicle.

According to an implementation of the present disclosure, there isprovided a kit comprising: i) the formulation comprising a) 0.1 to 50mg/mL Nebivolol hydrochloride with b) 0.1 to 300 mg/ml of a solubilizer;and ii) a liquid vehicle comprising (a) 5 to 400 mg/ml of a sweetener;(b) 0.1 to 100 mg/ml buffer; (c) 0.5 to 50 mg/ml of a preservative; and(d) 0.5 to 20 mg/ml of a flavoring agent, wherein the liquid vehicle iswater; and the pH of the formulation is in the range of 3 to 7.

According to an implementation of the present disclosure, there isprovided an oral pharmaceutical dosage form comprising a dosing unitcomprising the formulation as disclosed herein, wherein Nebivolol or apharmaceutically acceptable salt thereof is in a final concentrationequivalent to between 0.1 mg nebivolol HCl per ml liquid vehicle and 50mg nebivolol HCl per ml liquid vehicle.

According to an implementation of the present disclosure, there isprovided an oral pharmaceutical dosage form as disclosed herein, whereinthe dosage form is single dosage form or multiple dosage form. Inalternate implementation, there is provided an oral pharmaceuticaldosage form as disclosed herein, wherein the dosage form is singledosage form. In another alternate implementation, there is provided anoral pharmaceutical dosage form as disclosed herein, wherein the dosageform is multiple dosage form, wherein the multiple dosage form isselected from two of the single oral dosage form, three of the singleoral dosage form, four of the single oral dosage forms, or as per needthereof.

According to an implementation of the present disclosure, there isprovided a method of administration in an individual in need thereof,the method comprising: administering a first amount of the formulationas disclosed herein, wherein the first amount of the formulationcomprises Nebivolol or a pharmaceutically acceptable salt thereof in afinal concentration equivalent to between 0.1 mg nebivolol HCl per mlliquid vehicle and 50 mg nebivolol HCl per ml liquid vehicle.

According to an implementation of the present disclosure, there isprovided a method of administration in an individual in need thereof asdisclosed herein, wherein the first amount of the formulation is in asingle oral dosage form or multiple dosage form.

According to an implementation of the present disclosure, there isprovided a method of administration in an individual in need thereof asdisclosed herein, wherein the first amount is a single oral dosage formwithout a preservative, or a multiple oral dosage form with apreservative.

According to an implementation of the present disclosure, there isprovided a method of treating or preventing a condition, disorder, ordisease mediated by beta-blocking, the method comprising: administeringan effective amount of the formulation as disclosed herein or thepharmaceutical composition, to a subject in need thereof.

According to an implementation of the present disclosure, there isprovided a method of treating or preventing a condition, disorder, ordisease mediated by beta-blocking, wherein the condition, disorder, ordisease is selected from hypertension, or cardiovascular diseases.

According to an implementation of the present disclosure, there isprovided formulation described herein are administered chronically. Forexample, in one implementations, a Nebivolol oral liquid formulation isadministered as a continuous dose, i.e., administered daily to asubject. In other implementation, Nebivolol oral liquid formulationsdescribed herein are administered intermittently (e.g. drug holiday thatincludes a period of time in which the formulation is not administeredor is administered in a reduced amount).

According to an implementation of the present disclosure, there isprovided formulation described herein administered at a certain time ofday for the entire administration period. For example, a Nebivolol oralliquid formulation can be administered at a certain time in the morning,in the evening, or prior to bed. In certain instances, a Nebivolol oralliquid formulation is administered in the morning. In otherimplementation, a Nebivolol oral liquid formulation can be administeredat different times of the day for the entire administration period. Forexample, a Nebivolol oral liquid formulation can be administered on 8:00am in the morning for the first day, 12 pm noon for the next day oradministration, 4 pm in the afternoon for the third day oradministration, and so on.

According to an implementation of the present disclosure, there isprovided formulation described herein for treatment of certain diseasesor conditions (e.g., hypertension, heart failure, myocardial infarctionand the like) in a subject with a Nebivolol oral liquid formulationdescribed herein encompass additional therapies and treatment regimenswith other agents in some implementation. Such additional therapies andtreatment regimens can include another therapy, e.g., additionalanti-hypertensives, for treatment of the particular disease or conditionin some implementation. Alternatively, in other implementation,additional therapies and treatment regimens include other agents used totreat adjunct conditions associated with the disease or condition or aside effect from the Nebivolol oral liquid formulation in the therapy.

According to an implementation of the present disclosure, there isprovided formulation for use in combination with other pharmaceuticallyactive compound which includes but not limited to diuretics such asloop, thiazide, potassium-sparing, and the like, beta blockers such asmetoprolol, propanolol, pronethalol, and the like, alpha blockers suchas phentolamine, phenoxybenzamine, tamsulosin, prazosin, and the like,mixed alpha and beta blockers such as bucindolol, carvedilol, labetalol,calcium channel blockers such as dihydropyridines such as nifedipine,amlodipine, etc., dilitazem, verapamil and the like, angiotensin IIreceptor antagonists such as saralasin, losartan, eprosartin,irbesartan, valsartan, and the like), other ACE inhibitors such ascaptopril, lisinopril, quinapril, ramipril, enalapril, zofenopril, andthe like, aldosterone antagonists such as eplerenone, spironolactone andthe like, vasodilators such as hydralazine and the like, or alpha-2agonists such as clonidine, moxonidine, guanabenz and the like.

According to an implementation of the present disclosure, there isprovided a formulation which is therapeutically active and bioequivalentto Bystolic® tablets.

Although the subject matter has been described in considerable detailwith reference to certain examples and implementations thereof, otherimplementations are possible.

EXAMPLES

The disclosure will now be illustrated with the working examples, whichis intended to illustrate the working of disclosure and not intended totake restrictively to imply any limitations on the scope of the presentdisclosure. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood to one ordinaryperson skilled in the art to which this disclosure belongs. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice of the disclosed methods and compositions,the exemplary methods, devices and materials are described herein. It isto be understood that this disclosure is not limited to particularmethods, and experimental conditions described, as such methods andconditions may apply.

The oral liquid formulations of the present invention are found to betherapeutically active and bioequivalent to Bystolic® tablets.

The following examples serve to provide further appreciation of theinvention but are not meant in any way to restrict the effective scopeof the invention.

EXAMPLES Drug-Excipient Compatibility and Studies

Drug-Excipient compatibility study was carried with excipients such asmannitol, maltitol, dextrates, povidone, methyl paraben, propyl paraben,citric acid, sodium citrate, sodium saccharin. The study was carried outin clear glass vials with open air exposure at stress conditions 50° C.for 2 Weeks and 40° C./7.5% RH (relative humidity) for 1 month. Themajor impurity of Nebivolol i.e. desfluoro impurity was within thespecification limits and Nebivolol was found to be stable.

Solubility of Nebivolol was evaluated in various solubility enhancersand data is presented Table 1 given below:

TABLE 1 Solubility of Nebivolol HCl S. No Excipient (mg/ml) 1 Captisol(100 mg/ml) 12.45 mg 2 Cyclodextrin (100 mg/ml) 12.20 mg 3 Cyclodextrin(200 mg/ml)  27.4 mg 4 Propylene Glycol  8.3 mg 6 PEG 400  7.05 mg 7 PEG4000 (100 mg/ml)  2.08 mg 8 Labrasol  2.40 mg 9 Tween 20  4.3 mg 10Sodium lauryl sulfate    1 mg (10 mg/mL) 11 Purified water Insoluble

Granules were prepared using propylene glycol and cyclodextrin mixtureas granulating solvent and sorbitol powder, maltitol, dextrates, andsodium lauryl sulfate as powder blend to adsorb Nebivolol. The wetgranules were dried in oven at 50° C. and resultant granules werereconstituted with water to yield 1 mg/mL of Nebivolol solution. It wasobserved that the granules obtained using cyclodextrin as thesolubilizer, although showed the high solubility initially, however,when reconstituted, due to its high solubility character, the activecompound, i.e., nebivolol got precipitated. Thus, the selection ofsolubilizer was optimized.

Similarly, the use of sweetener in the formulation was optimized.Sweetener, such as lactose form Maillard adduct and hence not suitablefor use in the formulation. And acesulfame is not compatible with sodiumlauryl sulfate.

Alternatively, sorbitol powder or mixture of sorbitol powder and sodiumlauryl sulfate was granulated initially using propylene glycol andNebivolol (7 mg/ml) as granulating solvent. Various combination of theseformulations were prepared and tested for stability as given in Table 2below.

TABLE 2 S.No. Ingredient Granulating solvent 1 Sorbitol Powder propyleneglycol and Nebivolol (7 mg/ml) 2 Sorbitol Powder + SLS propylene glycoland Nebivolol (100 mg) (7 mg/ml) 3 Sorbitol Powder + SLS propyleneglycol and Nebivolol (200 mg) (7 mg/ml) 4 Sorbitol Powder propyleneglycol and Nebivolol (10 mg/ml) 5 Sorbitol Powder + SLS propylene glycoland Nebivolol (100 mg) (10 mg/ml) 6 Sorbitol Powder + SLS propyleneglycol and Nebivolol (200 mg) (10 mg/ml) 7 Dextrates + SLS propyleneglycol and (12 mg/ml)

After reconstitution, stability of the solution was tested and desfloroimpurity was within the specification limits and the solution was foundto be stable after 24 hrs at RT.

Stability at Different pH Condition

To evaluate the stability of Nebivolol in suitable liquid vehicle orsolubilizer at different pH conditions, pH stability study was performedusing 0.1N HCL/0.1N NaOH for pH adjustment. Propylene glycol was used assolubilizer to dissolve Nebivolol to prepare the stock solution. Thestock solution was added to water and adjusted the pH with 0.1N HCL/0.1NNaOH at different pH ranging from 3 to 7.

The solution of Nebivolol in propylene glycol was tested for desfluoroNebivolol impurity and found to be within the specification limits whentested 50° C. for 1M and 40° C./75% RH for 6M accelerated conditions andNebivolol was found to be stable.

Examples 1-4 Nebivolol Powder for Oral Solution

Table 3 provides the powder formulation of Nebivolol with othercomponents along with their weight percentages. The powder formulationcan be reconstituted in a liquid vehicle for administration as oralsolution.

TABLE 3 1 2 3 4 Ingredients % w/w Nebivolol HCl 0.87 0.88 0.87 0.88Sodium Lauryl Sulphate 8.77 8.84 8.77 8.84 Sorbitol Powder 87.71 88.4987.71 88.49 Sucralose 0.87 0.88 0.87 0.88 Sodium Benzoate 0.87 — — —Methyl Paraben Sodium — — 0.87 — Strawberry Flavour 0.87 0.88 0.87 —Orange Flavour — — — 0.88 Total 100 100 100 100

Preparation Process of the Formulation:

A solution of Nebivolol and sodium lauryl sulphate was prepared.Sorbitol powder and sucralose was blended and to this, a solution ofNebivolol and sodium lauryl sulphate was sprayed to obtain granules. Thewet granules were dried and blended with sodium benzoate, methyl parabensodium and strawberry flavour to obtain Nebivolol powder for solution.The power/granules obtained were blended with silicon dioxide and filledinto sachets and bottles.

Alternatively, the powder for solution was also prepared using spraydried method as described below:

A solution of Nebivolol and sodium lauryl sulphate was prepared andspray dried. To this, a mixture of sorbitol powder and sucralose wasadded, followed by sodium benzoate, methyl paraben sodium and strawberryflavour and blended to obtain Nebivolol powder for solution.

The compositions described herein are filled into Sachets (for singleuse) and HDPE bottles, each bottle contains 4.56 g of powder forsolution. Each bottle was reconstituted with 36 ml of purified water toprovide an oral solution formulation with specified concentration ofNebivolol. For Example, 0.88% (w/w) of powder upon reconstitution yields1 mg/mL solution.

Reconstitution Process of Powder for Oral Solution from HDPE Bottle

The reconstitution process include the following steps: 1. Shaken onebottle of powder for oral Solution (4.56 g) to loosen the powder, openedthe bottle and then removed the induction seal liner. 2. addedapproximately 36 mL of the water/liquid vehicle using a graduatedcylinder or a syringe measure to the powder. Tightly closed the HDPEbottle and shook vigorously by hand continuously for 3 minutes. 3.Allowed the bottle to sit for about 1 minute. 4. After reconstitution,40 mg of Nebivolol HCl is contained in 40 mL of the solution. Swirled(gently shook) before dispensing a dose.

Stability Testing of Powder for Oral Solution (POS)

The Powder for Oral Solution/suspension formulations described inExample 5 to 8 (Table 3) were stored at 40° C./75% RH and at 50° C. inopen exposure containers for 1M. After storage, the samples wereevaluated for assay, impurities, appearance, and odor. The POSformulations and corresponding solution formulations described hereinare found to be stable with minimum impurities and is compatible withthe pharmaceutical standards. Stability data of these formulations isgiven in Table 4 below:

TABLE 4 Test parameters 1 2 50° C. 40° C./75 RH 50° C. 40° C./75 RH 1M1M 1M 1M Assay 99 100 105 100 Related substances Desfloro imp 0.11 0.030.07 0.03 Unknown imp 0.18 0.19 0.22 0.14 Total imp 0.29 0.22 0.29 0.17Test parameters 3 4 50° C. 40° C./75 RH 50° C. 40° C./75 RH 1M 1M 1M 1MAssay 99 94 91 99 Related substances Desfloro imp 0.25 0.08 0.05 0.05Unknown imp 0.32 0.25 0.17 0.14 Total imp 0.57 0.33 0.22 0.19

Example 5 Nebivolol Powder for Oral Solution

TABLE 5 S. No Ingredient Qty/ml 1 Nebivolol HC1  1 mg 2 Sodium LaurylSulphate  10 mg 3 Sorbitol Powder 100 mg 4 Sodium Saccharin  2 mg 5Orange Flavour  2 mg 6 PVP K-90  10 mg

The powder formulation described above in Table 5 was prepared using theprocess similar to the one disclosed above for Example 1 (Table 3).

Example 6 Nebivolol Powder for Oral Solution

TABLE 6 Ingredients % w/w Nebivolol HCl 0.88 Sodium Lauryl Sulphate 8.8Xylitol 88.5 Sucralose 0.94 Strawberry Flavour 0.88 Total 100

Example 7

Nebivolol powder for oral solution

TABLE 7 Ingredients % w/w Nebivolol HCl 0.88 Sodium Lauryl Sulphate 5.6PEG 400 3.2 Xylitol 88.5 Sucralose 0.94 Strawberry Flavour 0.88 Total100

The powder formulation described above in Tables 6 and 7 were preparedusing the process similar to the one disclosed above for example 1(Table 3).

Example 8-10

Nebivolol Hydrochloride Powder Reconstituted with Liquid Vehicle

Nebivolol HCl (5 mg) powder was blended with sodium lauryl sulphate (10mg). The blend was filled in an HDPE bottle and reconstituted withliquid vehicle comprising the below ingredients. In Table 8, given belowis the composition of liquid vehicle used to reconstitute the powderedblend:

TABLE 8 Components 8 9 10 Artificial Grape Flavor 50 mg  75 mg 100 mgCitric Acid (anhydrous) 25 mg  35 mg  50 mg Sucralose 10 mg — — Xylitol— 200 mg 300 mg Saccharin sodium — — — D&C Yellow No. 10,  1 mg  0.5 mg 2 mg FD&C Red No. 40 Sodium Benzoate 10 mg —  20 mg Methyl paraben — 10 mg — Propylparaben —  1 mg — Purified water QS to  1 mL  1 mL  1 mL

Example 11—Nebivolol Oral Liquid

TABLE 9 S. No Ingredient Qty/ml 1 Nebivolol HCl  1 mg 2 Sodium LaurylSulphate  10 mg 3 Sorbitol Powder 100 mg 4 Sucralose  4 mg 5 OrangeFlavour  2 mg 6 PVP K-90  10 mg 7 Purified water Qs to 1 ml

Example 11 of Table 9 was prepared by the process described herein.Sodium lauryl sulphate was added to water, followed by Nebivolol,Sorbitol Powder, Sucralose, Orange Flavour, PVP K-90 and uniformly mixedto obtain solution.

The formulation yielded clear solution and was subjected to stresstesting at 50° C. for 2 W and under accelerated stability condition at40° C./75% RH for 2M. 30 cc HDPE bottles were used as container closuresystem. The data is presented in Table 10 below.

TABLE 10 Test Parameters 50° C. 40° C./75% RH Condition Initial 2W 2MAssay 100.5 96.5 99.5 pH 6.56 6.34 6.41 Related substances Desfloro imp0.01 0.03 0.03 Related comp-A 0.01 ND ND Unknown Imp ND 0.04 0.16 Totalimp 0.02 0.07 0.19

The formulation was to be stable in stress as well as acceleratedconditions. The formulation was found to have the least impurities andis compatible with the pharmaceutical standards.

The liquid formulations described in examples given below were preparedusing the process similar to the one disclosed above for example 10.

Example 12 Nebivolol Oral Liquid

TABLE 11 S. No Ingredient Qty (mg)/ml 1 Nebivolol HCl 0.87 2 PEG 40007.8 3 Maltitol 89.8 4 sodium benzoate 0.75 5 Strawberry Flavour 0.8 6Purified water Qs to 1 ml

Example 13—Nebivolol Oral Liquid

TABLE 12 S. No Ingredient Qty (mg)/ml 1 Nebivolol HCl 0.87 2 Poloxamer188 5.1 3 Maltitol 92.5 4 sodium benzoate 0.75 5 Strawberry Flavour 0.86 Purified water Qs to 1 ml

Example 14—Nebivolol Oral Liquid

TABLE 13 S. No Ingredient Qty (mg)/ml 1 Nebivolol HCl 0.87 2 Sodiumlauryl sulfate 8.7 3 Maltitol 89.2 4 sodium benzoate 0.75 5 StrawberryFlavour 0.7 6 Purified water Qs to 1 ml

Example 15—Nebivolol Oral Liquid

TABLE 14 S. No Ingredient Qty (mg)/ml 1 Nebivolol HCl 0.87 2 PEG 40009.3 3 Xylitol 88.1 4 sodium benzoate 0.91 5 Strawberry Flavour 0.91 6Purified water Qs to 1 ml

Example 16—Nebivolol Oral Liquid

TABLE 15 S. No Ingredient Qty (mg)/ml 1 Nebivolol HCl 0.87 2 PEG 40009.4 3 Sorbitol 88.1 4 sodium benzoate 0.85 5 Strawberry Flavour 0.85 6Purified water Qs to 1 ml

Example 17—Nebivolol Oral Liquid

TABLE 16 S. No Ingredient Qty (mg)/ml 1 Nebivolol HCl 1 2 Sodium LaurylSulphate 10 3 Sorbitol Powder 100 4 Sodium Saccharin 2 5 Orange Flavour2 6 PVP K-90 10 7 Purified water Qs to 1 ml

The formulations yielded clear solution, and was subjected to stresstesting at 50° C. for 2 W and under accelerated stability condition at40° C./75% RH for 2M with no or minimum impurities. 30 cc HDPE bottleswere used as container closure system. The data is presented Table 17below.

TABLE 17 Test Parameters 50° C. 40° C./75% RH Condition Initial 2W 2MAssay 101.2 98.9 100.5 pH 6.76 6.49 6.53 Related substances Desfloro imp0.03 0.04 ND Related comp-A ND ND ND Unknown Imp ND 0.06 0.11 Total imp0.03 0.10 0.11

The formulation was found to be chemically stable in stress as well asaccelerated conditions.

Example 18—Nebivolol Oral Liquid

TABLE 18 S. No Ingredient Qty (mg)/ml 1 Nebivolol HCl 1 2 Sodium LaurylSulphate 10 3 Sorbitol Solution 70/02B 200 4 Strawberry Flavour 2 5Purified water Qs to 1 ml

The formulation trial was subjected to stress testing at 50° C. for 2 Wand accelerated stability condition at 40° C./75% RH for 2M. The data ispresented in Table 19 below.

TABLE 19 Test Parameters 50° C. 40° C./75% RH Condition Initial 2W 2MAssay 100.9 99.9 100.3 pH 7.01 6.03 6.43 Related substances Desfloro imp0.03 0.05 0.04 Related comp-A ND ND ND Unknown Imp ND ND 0.19 Total imp0.03 0.05 0.23

The Formulation was found to be chemically stable in stress as well asaccelerated conditions with least or no impurities.

Example 19—Nebivolol Oral Liquid

TABLE 20 S. No Ingredients Qty/ml 1 Nebivolol HCl  1 mg 2 Sodium LaurylSulphate  10 mg 3 Citric acid anhydrous  0.4 mg 4 Sodium benzoate  1 mg6 Sorbitol Powder 100 mg 7 Sucralose  2 mg 8 Strawberry Flavour  2 mg 9Purified water Qs to 1 ml

The formulation trial yielded stable solution with a physicalobservation of clear colourless solution and it is evaluated foraccelerated stability condition at 40° C./75% RH. The data is presentedin Table 21 below.

TABLE 21 Test Parameters 40° C./75% RH Condition Initial 1M 2M Assay101.7 100.8 101.7 pH 4.55 4.52 4.54 Related substances Desfloro imp 0.040.02 0.04 Related comp-A ND ND ND Unknown Imp ND ND 0.02 Total imp 0.040.02 0.06

The above data shows the formulation is chemically stable underaccelerated conditions for 2 months with no impurities and met thepharmaceutical standards.

Although examples for the present disclosure have been described inlanguage specific to structural features and/or methods, it is to beunderstood that the appended claims are not limited to the specificfeatures or methods described herein. Rather, the specific features andmethods are disclosed and explained as exemplary implementations of thepresent disclosure.

ADVANTAGES OF THE PRESENT DISCLOSURE

The present disclosure provides a stable oral formulation comprising0.05 to 10% (w/w) of Nebivolol or a pharmaceutically acceptable saltthereof, 0.4 to 10% (w/w) of a solubilizer; and 5 to 90% (w/w) of asweetener, wherein the formulation has pH in the range of 3 to 7. Thepresent disclosure provides oral formulation in powder form which can bereconstituted with a suitable liquid vehicle. The formulation of thepresent disclosure are available for reconstitution with varied liquidvehicle selected from water, ethyl alcohol, glycerin, syrup, juices,beverages, or combinations thereof. The formulation of the presentdisclosure is stable and suitable for oral administration. The liquidformulation is stable for longer periods in the range of 30 days to 12months. The formulation can be administered as a single dosage or asmultiple dosage. The formulations of the present disclosure has improvedtaste and is suitable for pediatric and geriatric population and forthose who have difficulty in swallowing tablets or capsules. The liquidformulation of the present disclosure has increased solubility andstability, thereby improving their bioavailability and thereby thepharmaceutical activity of Nebivolol. The formulation of the presentdisclosure is a beta-blocker with β-adrenergic blocking ability. Theformulation of the present disclosure is a beta-blocker withβ-adrenergic blocking ability for use as a beta-blocker and/or fortreating abnormal blood pressures. The formulation of the presentdisclosure may also be used in combination with other pharmaceuticalactive compound selected from diuretics, beta blockers, alpha blockers,mixed alpha and beta blockers, calcium channel blockers, angiotensin IIreceptor antagonists, ACE inhibitors, aldosterone antagonists, oralpha-2 agonists. The present disclosure also provides a method ofadministration of the formulation to a subject in need thereof either insingle dosage or in multiple dosage. The formulation is stable for useas multiple dosage form. The present disclosure also provides a methodfor treating or preventing a condition, disorder, or disease mediated bybeta-blocking selected from hypertension, or cardiovascular diseases.

1-20. (canceled)
 21. An oral liquid formulation comprising: a. 0.1 to 2%(w/w) of nebivolol hydrochloride as the sole active ingredient; b. 5 to10% (w/w) of a solubilizer; c. 70 to 90% (w/w) of one or more sweetener;d. 0.5 to 1% (w/w) of a preservative; and e. a vehicle selected from thegroup comprising water, ethyl alcohol, glycerin, syrup and combinationsthereof.
 22. The oral liquid formulation of claim 21, wherein thesolubilizer is selected from cyclodextrin, propylene glycol,polyethylene glycol, polysorbate 20, polysorbate 80, sorbitanmonooleate, poloxamer, sodium lauryl sulfate and combinations thereof.23. The oral liquid formulation of claim 21, wherein the one or moresweetener is selected from the group comprising glucose, fructose,sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, lactitol,sorbitol, erythritol, trehalose, maltodextrin, polydextrose, glycerin,inulin, erythritol, acesulfame, and salts thereof, alitame, aspartame,neotame, sodium cyclamate, saccharin and salts thereof.
 24. The oralliquid formulation of claim 21, wherein the preservative is selectedfrom ascorbic acid, benzyl alcohol butylated hydroxyanisole, butylatedhydroxytoluene, sodium benzoate, sodium bisulfate, sodium metabisulfite,sodium sulfite, methyl paraben, propylparaben, benzoic acid, potassiumsorbate, and combinations thereof.
 25. The oral liquid formulation ofclaim 21, wherein the formulation comprises more than one vehicle. 26.The oral liquid formulation of claim 21, wherein the formulationcomprises 0.1 to 50 ml of the vehicle.
 27. The oral liquid formulationof claim 21, further comprising 0.1 to 1% (w/w) of a flavouring agent.28. The oral liquid formulation of claim 27, wherein the flavouringagent is selected from strawberry, cherry, grape, orange, peppermint,vanilla, bubble gum, or combinations thereof.
 29. The oral liquidformulation of claim 21, further comprising 0.025 to 5% of a buffer. 30.The oral liquid formation of claim 29, wherein the buffer is selectedfrom citric acid, sodium citrate, sodium tartarate, sodium acetate,sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodiumpyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate,trisodium phosphate or sodium phosphate, tripotassium phosphate, sodiumacetate, potassium metaphosphate, magnesium oxide, magnesium carbonate,magnesium silicate, calcium acetate, calcium glycerophosphate, calciumchloride, calcium hydroxide, calcium lactate, calcium carbonate, calciumbicarbonate, and other calcium salts.
 31. The oral liquid formulation ofclaim 21, wherein the formulation has a pH in the range of 3 to
 7. 32.The oral liquid formulation of claim 21, wherein the formulation isstable for a time period in the range of 30 days to one year.
 33. Theoral liquid formulation of claim 21, wherein the formulation has lessthan 1% (w/w) each of the impurities Desfluoro Nebivolol and4-Benzylated Nebivolol.
 34. The oral liquid formulation of claim 21,wherein the formulation has less than 5% (w/w) total impurities.
 35. Theoral liquid formulation of claim 21, wherein the formulation has lessthan 5% (w/w) total impurities after storage at ambient temperature forat least 30 days.
 36. The oral liquid formulation of claim 21, whereinthe formulation has greater than 95% (w/w) of the initial Nebivololamount after storage at ambient temperature for at least 30 days. 37.The oral liquid formulation of claim 21, wherein the formulation isstable at about 25±5° C. for a time period of at least one month to 12months.